Early detection of PARKINSON’S DISEASE, before the symptoms become obvious, will lead to early interventions to slow the disease process and improve the lives of people at risk for this disease. While there still is no cure for this disease, it has not been possible to even make a positive diagnosis until after symptoms have already appeared. By then, some estimates indicate that over 75% of the dopamine producing neurons in the patients’ brains have been destroyed. Medications do offer symptomatic relief of some of the symptoms, but early treatment could limit the damage to dopamine producing neurons and dramatically improve the quality of life for people with PARKINSON’S DISEASE.

A research team at Oxford University in the United Kingdom has used a new simple MRI scanning technique that has predicted PARKINSON’S DISEASE with very high accuracy. Standard MRI techniques are not sufficient to detect early changes in the brain that would signal development of the disease. Dr. Clare Mackay found an approach that allowed the team to study the connectivity strength of brain networks in the basal ganglia. Using his technique for resting state functional MRI (fMRI) the researchers compared the connectivity levels of 19 subjects with early stage PARKINSON’S DISEASE and 19 healthy control subjects. With 100% accuracy, they found a much lower level of connectivity in the brains of the subjects with PARKINSON’S DISEASE; it also picked up a small percentage of healthy people. So they repeated the study on a second group of subjects and the results were almost the same, sufficient to validate the results of the first study.

The technique is non-invasive; subjects are simply required to lie still in the scanner. Researchers hope that this new technique will become part of clinical practice and have the ability to allow physicians to predict which of their patients is at risk of developing PARKINSON’S DISEASE before any symptoms arise. The study was done with subjects known to be in the early stages, so more research will be done to refine the technique to be sensitive enough to predict risk for non-symptomatic subjects. Early detection combined with other new research discoveries may hold the key to better and earlier treatment, making life with PARKINSON’S DISEASE much easier.

Scientists Make Diseased Cells Synthesize Their Own Drug

By Eric Sauter

In a new study that could ultimately lead to many new medicines, scientists from the Florida campus of The Scripps Research Institute (TSRI) have adapted a chemical approach to turn diseased cells into unique manufacturing sites for molecules that can treat a form of muscular dystrophy.

“We’re using a cell as a reaction vessel and a disease-causing defect as a catalyst to synthesize a treatment in a diseased cell,” said TSRI Professor Matthew Disney. “Because the treatment is synthesized only in diseased cells, the compounds could provide highly specific therapeutics that only act when a disease is present. This means we can potentially treat a host of conditions in a very selective and precise manner in totally unprecedented ways.”

The promising research was published recently in the international chemistry journal Angewandte Chemie.

Targeting RNA Repeats

In general, small, low molecular weight compounds can pass the blood-brain barrier, while larger, higher weight compounds tend to be more potent. In the new study, however, small molecules became powerful inhibitors when they bound to targets in cells expressing an RNA defect, such as those found in myotonic dystrophy.

Myotonic dystrophy type 2, a relatively mild and uncommon form of the progressive muscle weakening disease, is caused by a type of RNA defect known as a “tetranucleotide repeat,” in which a series of four nucleotides is repeated more times than normal in an individual’s genetic code. In this case, a cytosine-cytosine-uracil-guanine (CCUG) repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities that, in turn, results in the disease.

In the study, a pair of small molecule “modules” the scientists developed binds to adjacent parts of the defect in a living cell, bringing these groups close together. Under these conditions, the adjacent parts reach out to one another and, as Disney describes it, permanently hold hands. Once that connection is made, the small molecule binds tightly to the defect, potently reversing disease defects on a molecular level.

“When these compounds assemble in the cell, they are 1,000 times more potent than the small molecule itself and 100 times more potent than our most active lead compound,” said Research Associate Suzanne Rzuczek, the first author of the study. “This is the first time this has been validated in live cells.”

Click Chemistry Construction

The basic process used by Disney and his colleagues is known as “click chemistry”—a process invented by Nobel laureate K. Barry Sharpless, a chemist at TSRI, to quickly produce substances by attaching small units or modules together in much the same way this occurs naturally.

“In my opinion, this is one unique and a nearly ideal application of the process Sharpless and his colleagues first developed,” Disney said.

Given the predictability of the process and the nearly endless combinations, translating such an approach to cellular systems could be enormously productive, Disney said. RNAs make ideal targets because they are modular, just like the compounds for which they provide a molecular template.

Not only that, he added, but many similar RNAs cause a host of incurable diseases such as ALS (Lou Gehrig’s Disease), Huntington’s disease and more than 20 others for which there are no known cures, making this approach a potential route to develop lead therapeutics to this large class of debilitating diseases.

People no longer have to blame their food cravings — and giving in to them — on poor self-control.

Now scientists are arguing that microbes living in the gut are responsible for manipulating eating behavior by causing cravings for food they favor for fitness or that suppress their competition. Alternatively, microbiota in the gut may send out signals via the vagus nerve to the brain to induce dysphoria and goad people into eating what the microbe needs whether it’s good for the host or not, a diverse group of researchers are suggesting.

“Bacteria within the gut are manipulative,” Carlo Maley, PhD, director, Center for Evolution and Cancer, University of California at San Francisco, states in a press release. “There is a diversity of interests represented in the microbiome, some aligned with our own dietary goals and others not.”

In their overview of eating behavior and the microbiome published online August 7, 2014 in BioEssays, Joe Alcock, MD, University of New Mexico, Albuquerque, and colleagues argue that certain microbes are highly dependent on the nutrient composition of the diet.

For example, Prevotella grows best on carbohydrates while dietary fiber provides a competitive advantage to Bifidobacteria. “Even microbes with a generalist strategy tend to do better on some combinations of nutrients than others,” the authors write, “and competition will determine which microbes survive.”

Microbes can manipulate host behavior in a variety of ways, but one way may be by “hijacking” the host’s nervous system. As the authors point out, evidence shows that microbes can have dramatic effects on behavior through the microbiome-gut-brain axis.

“The vagus nerve is a central actor in this communication axis, connecting the 100 million neurons in the enteric nervous system in the gut to the base of the brain at the medulla,” they explain. And, they add, enteric nerves have receptors that react to the presence of particular bacteria as well as to bacterial metabolites. Research has also shown that blockade or transection of the vagus nerve causes drastic weight loss while stimulation of its activity through norepinephrine appears to drive excessive eating behavior in satiated rats.

Other pathways through which microbes may influence host eating behavior is through secretion of hormones involved in mood and behavior, including dopamine and serotonin. Microbes may also manipulate eating behavior by altering receptor expression. Changes in taste receptor expression and activity have been reported following gastric bypass surgery, a procedure that changes gut microbiota and alters satiety and food preference, as the authors point out.

“Microbes have the capacity to manipulate behavior and mood through altering the neural signals in the vagus nerve, changing taste receptors, producing toxins to make us feel bad and releasing chemical rewards to make us feel good,” coauthor Athena Aktipis, PhD, Arizona State University, Phoenix, states in a press release.

“Together, these results suggest that microbes have opportunities to manipulate vagus nerve traffic in order to control host eating. Exerting self-control over eating choices may be partly a matter of suppressing microbial signals that originate in the gut.”

Happily, researcher add, the use of prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes can rapidly alter the microbiome within 24 hours of administration.

The study was funded by the National Institutes of Health, the American Cancer Society, the Bonnie D. Addario Lung Cancer Foundation, and the Institute for Advanced study in Berlin, Germany. The authors have disclosed no relevant financial relationships.

A pair of clinical researchers from the Department of Clinical Neurosciences and Mental Health, Faculty of Medicine at the University of Porto, in Porto, Portugal have written a scholarly article that refines and defines how the varying symptoms presented by people with PARKINSON’S DISEASE can be assessed and understood. They make a convincing argument that a “leap in concepts and a shift in research” is needed to enable therapeutic advances toward early treatment with specific neuroprotective agents for each unique presentation of symptoms.

In the past, PARKINSON’S DISEASE was thought to be caused by a loss of dopaminergic neurons in the substantia nigra. Positive diagnosis was delayed until motor symptoms were obvious and depended on the patient’s response to the ‘gold standard’, that is if the patient’s symptoms responded to levodopa. Positive response meant a diagnosis of PARKINSON’S, no response meant PARKINSONISM. Although patients had positive motor improvement responses to dopamine replacement, the results were only temporarily palliative; progression of the disease and the development of non-motor symptoms could not be halted. Many non-motor symptoms such as Rapid Eye Movement Sleep Disorder, loss of sense of smell, cognitive changes and mood problems may be present years before the motor symptoms present, and they involve neurological systems other than the dopamine system of the substantia nigra. These non-motor symptoms may well be precursors to the disease process, and appropriate treatments for them could delay or even halt the development of the motor symptoms.

Studies of the genetics of PARKINSON’S DISEASE have found only a few examples of heritable forms of the disease. But studies of those same genes have yielded further information of the specific roles each of those genes play in modifying or affecting various cellular processes that occur in the development of the disease. The alpha-synuclein gene (SNCA) when mutated, causes aggregations of alpha-synuclein but also has interactions with the PARK genes, with the LRRK2 or the GBA genes. The results of those various and individual interactions contribute significant differences in their presentation in the clinical and neuropathological features of the disease.

Post mortem examinations have shown that patients whose motor symptoms presented early and who had a good response to levodopa but then had a more rapid decline, including dementias, had mutations in the SNCA genes. Patients who had a slower progression of motor symptoms but had more dystonia or tremors usually carried LRRK2 mutations. GBA mutations were found in brains of patients who had early onset with both sides of the body equally affected and also more pronounced neuropsychiatric issues, such as symptoms often being found in Alzheimer’s disease patients. Another unique mutation in the VPS35 gene causes motor complications that get a significant benefit from dopamine replacement and no diminishment of cognitive function. PARK2 carriers had a slower progression of symptoms and responded well to dopamine replacement, but frequently were prone to develop dyskinesias. Dementia was rare in these cases and synucleinopathy was not found in post mortem examinations; however, much deterioration of the substantia nigra was seen.

The above descriptions show that many share multiple symptoms with PARKINSON’S DISEASE, but also demonstrate many differences in clinical presentation, imaging and other neuropathological features. While they may share a common response to dopamine replacement, they may, indeed, be manifestations of other similar but different diseases. There currently are no reliable biomarkers that can accurately predict the onset of the disease or distinguish one form from another, or even monitor its progression. Given the differing symptom presentations, genetics and pathological findings, it is likely that PARKINSON’S DISEASE is not a single disease, but an umbrella that covers multiple, but similar diseases.

A non-traditional physics lab at Michigan State University has been working to advance medical solutions by combining physics and biochemistry. And it is working.

Lisa Lapidus, Ph.D., who is an associate professor of physics and astronomy, was fascinated by the idea that eating spicy food could slow the development of PARKINSON’S DISEASE. So she undertook studies of the spice, curcumin, which is thought to be the major substance in tumeric often used in South East Asian curries and cooking. It has a reputation for being anti-inflammatory and helpful for osteoarthritis. Unfortunately, she found that the molecule of curcumin, while helpful in other diseases, was too large to pass across the blood brain barrier.

In doing that research, she learned about protein aggregations and studied the rate at which proteins mis-fold. Using lasers, she was able to study the rate at which proteins formed aggregates. She found that if the proteins fold either faster or slower than the rate at which they bump into each other, then aggregation is slow. However, if they are bumping into each other at the same rate as when they are reconfiguring, then they will swiftly clump together causing aggregation and neurodegeneration follows.

When a person with PARKINSON’S presents with the symptoms, the process of protein aggregation has already begun. However, there is a patented molecule, called CLR01, which mimics the action of curcumin to prevent protein aggregates from forming. And CLR01 is a small enough molecule that it can cross the blood brain barrier. This small CLR01 molecule can be sent to its target site and will speed up the reconfiguration of the proteins and actually stop the early stages of them forming aggregates. This molecule attaches to the amino acid lysine, which is part of the protein, and acts like a claw or a pair of molecular tweezers to prevent binding with other proteins.

This CLR01 molecule used in this way to prevent aggregations of proteins from forming in the brain is an excellent candidate for a new drug that can be used to stop PARKINSON’S DISEASE early in the game and keep it from becoming the disabling disease. Hopefully, this research will move to the clinical trial stages soon and become a valuable resource for treating not only PARKINSON’S DISEASE, but other neurodegenerative diseases too.

Mood and Cognition Adversely Affected by Dopamine in Depressed People with PD

A new research study from the University of Kentucky College of Medicine and the Sanders Brown Center on Aging has shown some information about depression and PARKINSON’S DISEASE that was not typically expected. Lee Blonder, Ph.D. used a small group of 28 subjects, all with PARKINSON’S DISEASE, 10 of whom were depressed and 18 who were not to examine the effects of dopamine replacement on cognitive function and depression. HIs expectations were that cognitive function would improve for both depressed and non-depressed subjects with the addition of dopamine. To his surprise, this did not prove to be true.

All of the subjects underwent a baseline series of cognitive testing and tests to measure the severity of their depression. Then they were all retested both with and without their regular dopamine replacement therapies. Subjects who were depressed were found to have poorer performance on three measures of the cognitive testing when taking dopamine replacement than without the dopamine. Mood of the depressed subjects was also worse on dopamine. For subjects that did not have depression, performance on cognitive testing improved on dopamine therapy and their mood was stable.

The results of this study raise concerns about treatment options that may compromise the mental health and cognitive functioning of depressed patients with PARKINSON’S DISEASE. Dr. Blonder cautions that this is a very small preliminary study and should not be used to change treatment plans until additional larger studies confirm his findings. Depression is very common in PARKINSON’S patients, with perhaps 40% of patients affected.

As she continues to pursue her fascination with the creative process of her Parkinson’s patients treated with dopamine replacement therapies, Dr. Rivka Inzelberg has just published a new paper in the Annals of Neurology journal. Dr. Inzelberg is associated with the Department of Neurology at the Sheba Medical Center and the Sackler Faculty of Medicine at Tel Aviv University in Israel. Several years ago, she noticed that at holiday time, when patients brought her small gifts, the gifts were no longer of the chocolates and wine, but small artistic creations produced by the patients themselves.

Her research lead her to the connection between dopamine and behavior and its involvement with the “reward system”. It is also associated with impulse control disorders (ICD) and stories of how dopamine replacement therapies have triggered destructive bouts of gambling or unrestrained shopping sprees abound. But there is also a creative impulse in some patients that has been discovered or enhanced by this therapy. And this artistic creativity spans all creative genres, from painting and drawing, to writing poetry and more. Dr. Inzelberg speculated that perhaps the loosening of the impulse control helps patients to find the courage to express their talents or helps them express their talents in different ways, but her creative patients did not all fit the impulse control model. So she designed a study “to identify features of creative thinking in PD patients and examine whether creativity in PD patients treated with dopaminergic therapy is an expression of ICD or a distinct phenomenon.”

Together with her research team, they recruited 27 Parkinson’s patients and 27 healthy, age matched controls. Both groups met certain education requirements, had similar cognitive testing results and were screened to rule out depression. Both groups underwent a battery of testing. Verbal and creativity tests consisted of Verbal Fluency, Remote Association Test, the Tel-Aviv University Creativity Test, and a test of novel metaphors in which they must determine if the meaning of multiple two word expressions is literal, conventional, novel or meaningless. This test in particular requires a semantic flexibility or a creative sensibility as compared to simple meaning retrieval of words already in the vocabulary. Subjects were also given tests to evaluate for any symptoms of Impulse Control Disorder.

The subjects in the Parkinson’s side of the study were then further sub-divided into three groups, based on the amount of levodopa (dopamine replacement) they were receiving, from highest, mid level or lowest. The researchers found a “significantly higher amount of creative responses” among the group with the highest dose of levodopa.

Further analysis of the results showed a significantly enhanced creativity among the Parkinson’s patients compared to the healthy controls. There was also no correlation between creativity and impulse control disorder, which was one of the main questions this study sought to resolve.

The results suggest that the creative process that requires originality and flexibility is supported by a distinct neurological process, and that dopamine is involved in enhancing verbal flexibility and visual creativity. The researchers suggest that the role of dopamine in the creative process may enable the brain to filter out unnecessary or irrelevant stimuli while at the same time improving divergent thinking and creating more associated meanings.

The authors of this study stress that it was done on a small population of Parkinson’s patients who were already receiving dopamine therapy. Further studies could follow subjects from early stages without dopamine replacement to later stages with dopamine replacement and monitor changes in creativity related to dosage changes. They also feel that it is perhaps only a subset of the Parkinson’s population that has a strong creativity process.

According to Aleksander Videnovic, M.D., from the Clinical Neurological Research Institute, Massachusetts General Hospital and Harvard Medical School in Boston, “Sleep disturbances are among the most common and disabling non-motor manifestations of PARKINSON’S DISEASE, affecting as many as 90% of patients.”

Sleep disturbance definitely changes the quality of life, leading to mood changes, depression, and irritability. Lack of sleep can hamper one’s awareness and lead to accidents and falls. And it is not only the patient who suffers…the caregiver’s life is turned upside down, too.

The biological clock plays an important role in other aspects of our daily lives besides affecting sleep patterns. It sets the rhythm for the hormones responsible for hunger and metabolism. It impacts heart function and can even affect the body’s immune response and how it fights infection. When sleep patterns are disrupted mood can be affected by the response of serotonin to the relation to light-dark cycles. People with seasonal affective disorder (SAD) become depressed when the days become shorter but improve when serotonin levels increase due to more available light during longer days.

Light therapy, using bright lights, has been effective in helping to relieve depression and seasonal affective disorder. Light therapy, using infrared light has also shown some effectiveness in relieving chronic pain. Because there is much clinical evidence showing positive beneficial benefit of exposure to light in both animal and human models, Dr. Videnovic designed a study for people with PARKINSON’S to evaluate their responses to light therapy.

He chose a group of 30 PARKINSON’S patients, 13 men and 17 women, who were experiencing daytime sleepiness and randomly assigned them to either a bright light therapy or a red light therapy. Sessions for both light therapy groups consisted of exposure to either bright light or red light for one hour twice a day for a period of two weeks. Subjects received their usual medications during the study. At baseline before treatment and then at the end of two weeks of treatment they were evaluated using several sleep study scales including the Epworth Sleepiness Scale (ESS) as well as the United Parkinson’s Disease Rating Scale (UPDRS) and test to measure depression. Two weeks after the end of the treatment, they were also re-evaluated.

Both groups showed only modest improvement, but the bright light therapy group showed a statistically significant improvement with average ESS score of 4.75 to the red light group score of 1.79. The bright light group also showed an improvement in the UPDRS score, which continued a small upward improvement even after two weeks.

This is a rather small study, but the results are definitely encouraging. This is a very early investigation and there may be other methods of bright light treatment that might bring more improvement. Any improvement in sleep that helps the body clock also has positive benefits on neurological functions. Further study is needed to optimize the benefits of light therapy for people with PARKINSON’S who have sleep problems and excessive daytime sleepiness.

The authors of this study presented their research results at the Annual Meeting of the American Academy of Neurology (AAN) as Abstract 13-2.004 on April 28, 2014.

Can PARKINSON’S Be Helped with Acupuncture?Several studies have been undertaken to measure the improvement of PARKINSON’S DISEASE symptoms using acupuncture. They all report some benefit, but perhaps measuring results of Chinese medical philosophy by the standards of Western medical philosophy is a bit like comparing apples and oranges!

Chinese medicine, from which acupuncture is derived, sees human disease as an issue of imbalance of internal flows of energy within the body. When there is an imbalance, there will be multi-organ disharmonies. Chinese medicine attempts to restore balance to organs and organ relationships and to regain normal function and not simply treat the symptoms. Acupuncture is only one way of helping to restoring balance.

Western medicine, and in movement disorders especially, looks at symptoms in an objective manner, developing scales by which to measure the way symptoms manifest. The Unified Parkinson’s Disease Rating Scale (UPDRS) consists of several rating scales covering multiple aspects of PARKINSON’S symptoms, and is used to help neurologists determine the severity or progression of the disease symptoms. While it attempts to be objective, it requires training and experience and is based on the physicians’ observations and the patients’ responses.

In all the studies, subjects who received acupuncture reported positive responses and felt some improvement in some of their symptoms. Sleep was improved and pain decreased, and swallowing issues were sometimes improved. The feelings of fatigue that plague so many people with PARKINSON’S DISEASE were reduced significantly, leading to better energy and improved enjoyment of life. While Western neurologists may consider these reports to be subjective and not objective, to the people with PARKINSON’S, the relief is very real.

A new study from the University of Arizona has published the results in Neurology, the journal of the American Academy of Neurology. This time, the research team was able to measure objective improvements in balance and gait. These researchers used electroacupuncture, which places the acupuncture needles in the same meridians but uses a small electrical current passed between two needles. Subjects in this trial were divided into two groups, one receiving actual treatment and the other receiving sham treatment. Subjects in each group received treatment that lasted for 30 minutes once a week for three weeks. Multiple measurements of balance and gait were measured under various conditions. The control group did not show any improvement but the acupuncture group showed an improvement of 31% in balance, gait speed increased by 10% and length of stride improved 5%

Hopefully, more studies similar to this will be done soon to verify the results. Acupuncture may be a good alternative treatment for people with PARKINSON’S DISEASE, to be used in addition to medications and therapies prescribed by their neurologists. Patients should always discuss any alternative treatments they are interested in trying with their doctors and keep them informed of supplements or herbal preparations they are using in addition to their prescribed medications.

A lesion in the visual cortex renders some people technically blind. While their actual eyes are still functional and can perceive the source of light or even discern and emotional expression on someone’s face, they are still considered legally blind. A person with PARKINSON’S DISEASE, may have intact eye function and no lesion in the visual cortex, but may be unable to perceive the emotion on another’s face or grasp an object that is moving.

Dr. Nico Diederich has been studying vision deficits in PARKINSON’S DISEASE for many years. He is a Clinical Senior Researcher at the University of Luxembourg Centre for Systems Biomedicine and is presently a visiting scholar at Rush University Medical Center in Chicago, IL. Together with three more researchers from Rush, they recently published a research study entitled “Are patients with Parkinson’s disease blind to blindsight?” in the scientific journal Brain that explains their concept for understanding visual impairment in PARKINSON’S DISEASE.

Dr. Diederich describes blindsight as the ability of the technically blind to accurately perceive a source of light or detect a rapid motion or even an emotional expression on someone’s face…without being consciously aware of “seeing”. He describes it as similar to a reflex. In “blindsight”, visual stimuli can pass through lower areas of the brain and still be processed to turn in a response. His research on PARKINSON’S DISEASE has found that although PARKINSON’S patients have no problems with their general vision, their responses are impaired; hence he calls them “blind to blindsight”.

Approximately a third of people with PARKINSON’S also experience hallucinations, when small, involuntary movements flutter in the corner of the eye may be mistaken for people or animals. Taken together, these visual impairments with a mistaken perception or a slow response time can greatly hinder the patient’s ability to drive and definitely negatively affect their quality of life.

“We have analyzed all known visual impairments in PARKINSON’S patients and compared them with the “blindsight” syndrome. We could show that mostly evolutionary old brain networks are impaired and underlie the visual impairments observed in PARKINSON’S DISEASE, states Dr. Diederich.

Glenn Stebbins, Ph.D. and Christopher G. Goetz, M>D> from Rush University Medical Center in Chicago and Christine Schiltz, PHD, from the University of Lusembourg contributed to this research.

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